12-123671146-G-A

Variant names:

• chr12-123671146-G-A
• rs7980060
• NM_024809.5:c.-95G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024809.5(TCTN2):​c.-95G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,228,970 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (164 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (115 hom.)
• Consequence: TCTN2 NM_024809.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.902
• Publications: 1 publications found

Genes affected

TCTN2 (HGNC:25774): (tectonic family member 2) This gene encodes a type I membrane protein that belongs to the tectonic family. Studies in mice suggest that this protein may be involved in hedgehog signaling, and essential for ciliogenesis. Mutations in this gene are associated with Meckel syndrome type 8. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

TCTN2 Gene-Disease associations (from GenCC):

• Joubert syndrome 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• Meckel syndrome, type 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-123671146-G-A is Benign according to our data. Variant chr12-123671146-G-A is described in ClinVar as Benign. ClinVar VariationId is 307541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024809.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.-95G>A		5_prime_UTR	Exon 1 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.-95G>A		5_prime_UTR	Exon 1 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.-95G>A		5_prime_UTR	Exon 1 of 17	NP_001397918.1	A0A7P0T8X4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.-95G>A		5_prime_UTR	Exon 1 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.-95G>A		5_prime_UTR	Exon 1 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.-95G>A		5_prime_UTR	Exon 1 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3803 AN: 152188 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00270 AC: 2903 AN: 1076664 Hom.: 115 Cov.: 14 AF XY: 0.00234 AC XY: 1277 AN XY: 544572

African (AFR) AF: 0.0932 AC: 2367 AN: 25410

American (AMR) AF: 0.00382 AC: 135 AN: 35364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23264

East Asian (EAS) AF: 0.00 AC: 0 AN: 34452

South Asian (SAS) AF: 0.000246 AC: 18 AN: 73192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37628

Middle Eastern (MID) AF: 0.00385 AC: 19 AN: 4932

European-Non Finnish (NFE) AF: 0.0000956 AC: 76 AN: 794938

Other (OTH) AF: 0.00607 AC: 288 AN: 47484

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152306 Hom.: 164 Cov.: 32 AF XY: 0.0239 AC XY: 1781 AN XY: 74468

African (AFR) AF: 0.0875 AC: 3634 AN: 41548

American (AMR) AF: 0.00810 AC: 124 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68034

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00912 Hom.: 53

Bravo AF: 0.0285

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 24 (1)
-	-	1	Meckel syndrome, type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.2
DANN	Uncertain	0.98
PhyloP100		0.90
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7980060; hg19: chr12-124155693;